6-29942594-C-G

Variant names:

• chr6-29942594-C-G
• rs2230954
• NM_002116.8:c.41C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_002116.8(HLA-A):​c.41C>G​(p.Ser14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S14L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-A NM_002116.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.59
• Publications: 23 publications found

Genes affected

HLA-A (HGNC:4931): (major histocompatibility complex, class I, A) HLA-A belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen so that they can be recognized by cytotoxic T cells. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. More than 6000 HLA-A alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]

ENSG00000227766 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31378055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-A	NM_002116.8	c.41C>G	p.Ser14Trp	missense_variant	Exon 1 of 8	ENST00000376809.10	NP_002107.3
LOC124901298	XR_007059541.1	n.813+2187G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-A	ENST00000376809.10	c.41C>G	p.Ser14Trp	missense_variant	Exon 1 of 8	6	NM_002116.8	ENSP00000366005.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 104268 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1002368 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 499660

African (AFR) AF: 0.00 AC: 0 AN: 23528

American (AMR) AF: 0.00 AC: 0 AN: 22088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16356

East Asian (EAS) AF: 0.00 AC: 0 AN: 26232

South Asian (SAS) AF: 0.00 AC: 0 AN: 62278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 770134

Other (OTH) AF: 0.00 AC: 0 AN: 42616

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 104268 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 50196

African (AFR) AF: 0.00 AC: 0 AN: 29004

American (AMR) AF: 0.00 AC: 0 AN: 9276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2380

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 3404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47636

Other (OTH) AF: 0.00 AC: 0 AN: 1402

Alfa AF: 0.00 Hom.: 78

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.092	T;T;T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.25	.;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-4.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;D;N;.
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;.;.
Sift4G	Uncertain	0.019	D;D;D;D;.
Polyphen		0.95	P;D;P;D;.
Vest4		0.22
MutPred		0.49		Gain of catalytic residue at L12 (P = 0.0022);Gain of catalytic residue at L12 (P = 0.0022);Gain of catalytic residue at L12 (P = 0.0022);Gain of catalytic residue at L12 (P = 0.0022);Gain of catalytic residue at L12 (P = 0.0022);
MVP		0.51
MPC		0.44
ClinPred		0.95	D
GERP RS		-1.4
PromoterAI		-0.14	Neutral
Varity_R		0.13
gMVP		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2230954; hg19: chr6-29910371;